LX-4211
(Synonyms: 索格列净,LX4211;LX 4211) 目录号 : GC15088
LX-4211是一种口服的强效双重SGLT2/1抑制剂，对SGLT1和SGLT2的IC50值分别为36nM和1.8nM。
Cas No.:1018899-04-1
Sample solution is provided at 25 µL, 10mM.
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LX-4211 is an oral, potent dual SGLT2/1 inhibitor, with IC50 values of 36nM and 1.8nM for SGLT1 and SGLT2, respectively[1][2]. LX-4211 enhances urinary glucose excretion by inhibiting SGLT2 and reduces gastrointestinal glucose absorption by inhibiting SGLT1, thereby effectively lowering blood glucose levels[3][4]. LX-4211 is commonly used in diabetes-related research[5][6].
In vitro, treatment of porcine coronary artery cultured endothelial cells (ECs) with LX-4211 (10nM) for 30 minutes before the subsequent incubation in normo glucose or high glucose (HG: 25mmol/L) for 24 hours reduced glucose uptake stimulated by HG, and decreased ECs senescence markers and oxidative stress, upregulated eNOS expression and NO formation, and reduced the expression of VCAM-1, tissue factor, and the local angiotensin system[7].
In vivo, Oral treatment of nonobese diabetes-prone mice with cyclophosphamide-induced T1D with LX-4211(orally;2/30mg/kg/day)for 22 days significantly decreased blood glucose levels and A1c levels without increasing the rate of hypoglycemia measurements[8]. Oral administration of LX-4211 (60mg/kg)in mice reduces intestinal glucose absorption by inhibiting SGLT1, increases the release of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), while reducing the release of glucose-dependent insulinotropic polypeptide (GIP) and fluctuations in blood glucose levels during the 6 hours after a glucose-containing meal[4].
References:
[1] Zambrowicz, B., Freiman, J., Brown, P. M., Frazier, K. S., Turnage, A., Bronner, J., Ruff, D., Shadoan, M., Banks, P., Mseeh, F., Rawlins, D. B., Goodwin, N. C., Mabon, R., Harrison, B. A., Wilson, A., Sands, A., & Powell, D. R. (2012). LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clinical pharmacology and therapeutics, 92(2), 158–169.
[2] Goodwin, N. C., Ding, Z. M., Harrison, B. A., Strobel, E. D., Harris, A. L., Smith, M., Thompson, A. Y., Xiong, W., Mseeh, F., Bruce, D. J., Diaz, D., Gopinathan, S., Li, L., O'Neill, E., Thiel, M., Wilson, A. G., Carson, K. G., Powell, D. R., & Rawlins, D. B. (2017). Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes. Journal of medicinal chemistry, 60(2), 710–721.
[3] Goodwin, N. C., Mabon, R., Harrison, B. A., Shadoan, M. K., Almstead, Z. Y., Xie, Y., Healy, J., Buhring, L. M., DaCosta, C. M., Bardenhagen, J., Mseeh, F., Liu, Q., Nouraldeen, A., Wilson, A. G., Kimball, S. D., Powell, D. R., & Rawlins, D. B. (2009). Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. Journal of medicinal chemistry, 52(20), 6201–6204.
[4] Powell, D. R., Smith, M., Greer, J., Harris, A., Zhao, S., DaCosta, C., Mseeh, F., Shadoan, M. K., Sands, A., Zambrowicz, B., & Ding, Z. M. (2013). LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. The Journal of pharmacology and experimental therapeutics, 345(2), 250–259.
[5] Herat, L. Y., Matthews, J. R., Hibbs, M., Rakoczy, E. P., Schlaich, M. P., & Matthews, V. B. (2023). SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes. iScience, 26(8), 107260.
[6] Bhatt, D. L., Szarek, M., Steg, P. G., Cannon, C. P., Leiter, L. A., McGuire, D. K., Lewis, J. B., Riddle, M. C., Voors, A. A., Metra, M., Lund, L. H., Komajda, M., Testani, J. M., Wilcox, C. S., Ponikowski, P., Lopes, R. D., Verma, S., Lapuerta, P., Pitt, B., & SOLOIST-WHF Trial Investigators (2021). Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. The New England journal of medicine, 384(2), 117–128.
[7] Khemais-Benkhiat, S., Belcastro, E., Idris-Khodja, N., Park, S. H., Amoura, L., Abbas, M., Auger, C., Kessler, L., Mayoux, E., Toti, F., & Schini-Kerth, V. B. (2020). Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence. Journal of cellular and molecular medicine, 24(3), 2109–2122.
[8] Powell, D. R., Doree, D., Jeter-Jones, S., Ding, Z. M., Zambrowicz, B., & Sands, A. (2015). Sotagliflozin improves glycemic control in nonobese diabetes-prone mice with type 1 diabetes. Diabetes, metabolic syndrome and obesity : targets and therapy, 8, 121–127.
LX-4211是一种口服的强效双重SGLT2/1抑制剂，对SGLT1和SGLT2的IC50值分别为36nM和1.8nM[1][2]。LX-4211通过抑制SGLT2增强尿糖排泄，并通过抑制SGLT1减少胃肠道葡萄糖吸收，从而有效地降低血糖水平[3][4]。LX-4211通常用于糖尿病相关研究[5][6]。
在体外实验中，用10nM LX-4211 处理猪冠状动脉培养的内皮细胞（ECs）30分钟后，再在正常葡萄糖或高葡萄糖（HG：25mmol/L）条件下继续孵育24小时，可以减少由高葡萄糖刺激引起的葡萄糖摄取，并降低内皮细胞衰老标志物和氧化应激水平，上调eNOS的表达和NO的形成，并减少VCAM-1、组织因子和局部血管紧张素系统的表达[7]。
在体内，用LX-4211（口服；2/30mg/kg/day）治疗环磷酰胺诱导的非肥胖糖尿病易感小鼠22天，显著降低了血糖水平和糖化血红蛋白（A1c）水平，而没有增加低血糖测量的比率[8]。在小鼠中，口服LX-4211（60mg/kg）可在含糖餐后6小时内通过抑制SGLT1减少肠道葡萄糖吸收，增加胰高血糖素样肽-1（GLP-1）和肽YY（PYY）的释放，并减少葡萄糖依赖性促胰岛素多肽（GIP）的释放以及血糖水平的波动[4]。
| Cell experiment [1]: | |
Cell lines | Porcine coronary artery cultured endothelial cells (ECs) |
Preparation Method | Porcine hearts were collected from the local slaughterhouse. Left circumflex coronary arteries were excised, cleaned and flushed with PBS without calcium to remove remaining blood. For immunofluorescence staining, coronary artery segments with endothelium were incubated in RPMI containing a normal glucose concentration (NG: 11.1mmol/L) supplemented with fungizone (2.5μg/mL), penicillin (100U/mL), streptomycin (100μg/mL), HEPES (100mmol/L), in the absence or presence of empagliflozin (100nmol/L) or LX-4211(10nM) for 30 minutes before the subsequent incubation in normal glucose or high glucose (HG: 25mmol/L) for 24 hours. Thereafter, segments were washed with PBS before being embedded in FSC22 Frozen section medium and frozen in liquid nitrogen. |
Reaction Conditions | 10nM; 30min |
Applications | LX-4211 markedly reduced the level of oxidative stress in ECs. |
| Animal experiment [2]: | |
Animal models | Female NOD/ShiLtJ mice |
Preparation Method | Diabetic mice were randomized by body weight and blood glucose level into four treatment groups: 0.2U insulin/vehicle, 0.05U insulin/vehicle, 0.05U insulin/2mg/kg LX-4211 or 0.05U insulin/30mg/kg LX-4211. On day –1, while under isoflurane anesthesia, all mice were implanted subcutaneously with an Alzet micro-osmotic pump (model 1004, 4 weeks’ duration) delivering insulin in the form of Humulin R at doses of either 0.05U/day or 0.2U/day. On the next day (study day 1), all mice received their first daily dose of either vehicle (0.1% Tween 80 in water) alone or vehicle containing LX-4211, chemical structure (2S,3R,4R,5S,6R)-2-(4-chloro-3-[4-ethoxybenzyl] phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. LX-4211 was delivered once in the afternoon by oral gavage at a dose of either 2mg/kg or 30mg/kg in a 10mL/kg total volume; these doses were chosen because in past mouse studies, 2mg/kg had a half-maximal effect and 30mg/kg a maximal effect on urinary glucose excretion. |
Dosage form | 2, 30mg/kg/day for 22 days; p.o. |
Applications | LX-4211(orally; 2/30mg/kg/day)for 22 days significantly decreased blood glucose levels and A1c levels without increasing the rate of hypoglycemia measurements. |
References: | |
| Cas No. | 1018899-04-1 | SDF | |
| 别名 | 索格列净,LX4211;LX 4211 | ||
| 化学名 | (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-trio | ||
| Canonical SMILES | CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)SC)O)O)O)Cl | ||
| 分子式 | C21H25ClO5S | 分子量 | 424.94 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,Ethanol: 30 mg/ml,Ethanol:PBS(pH 7.2) (1:1): 0.5 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3533 mL | 11.7664 mL | 23.5327 mL |
| 5 mM | 0.4707 mL | 2.3533 mL | 4.7065 mL |
| 10 mM | 0.2353 mL | 1.1766 mL | 2.3533 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
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